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Prof. Dr. C.E. Müller

University of Bonn

Pharmaceutical Institute

Department of Pharmaceutical & Medicinal Chemistry

An der Immenburg 4

D-53121 Bonn

 

Tel.: 0228/73-2301

Tel. int.: +49-228-73-2301

Fax.: 0228/73-2567

Fax int.: +49-228-73-2567

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Corona research

June 2021

 

Prof. Christa E. Müller and Prof. Michael Gütschow (both Pharm. & Med. Chemistry, Pharmaceutical Institute) will receive up to 500,000 Euros over three years from the VW Foundation to support their corona research. The two scientists are investigating drugs against SARS-CoV-2 and other corona viruses. The drug target is the main protease of the corona viruses. A great advantage of this target is that practically no mutations are known. With the money, the team can continue the research that has so far been financed from their own funds. For example, studies on pharmacokinetics and toxicity will be carried out and important drug compounds will be optimised. We wish both scientists and their team every success with their research!

Link to the news

March 2021

 
The main protease of SARS-CoV-2 (Mpro) is essential for the replication of the corona virus and is a significant drug target. Its blockade can inhibit the replication of the virus. Small drug molecules as inhibitors of this protease are therefore a promising strategy against COVID-19. The research groups of Prof. Christa E. Müller and Prof. Michael Gütschow (both Pharmaceutical Institute, Pharm. & Med. Chemistry) identified appropriate substructures and assembled two types of compounds that block the Mpro of SARS-CoV-2. These rationally designed inhibitors are promising candidates for the further development of antiviral drugs against COVID-19. The ultimate goal is to obtain drugs for the treatment of COVID-19. The results were published in an article entitled “Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors” in the journal Angewandte Chemie

 

image_large (2).jpg

 

Main protease of the coronavirus with one of the newly developed inhibitors in the active centre. The individual domains of the protein are shown in different colours, the inhibitor in pink.

© V. Namasivayam/Pharmaceutical

Institute/University of Bonn

 

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Teammembers in front of the Pharmaceutical Institute Bonn
from left to right: Miriam Diett, Laura Schäkel, Dr. Vigneshwaran Namasivayam, Katharina Sylvester, Ghazl Al Hamwi, Prof. Dr. Christa E. Müller, Prof. Dr. Michael Gütschow, Julian Breidenbach, Maria Zyulina, Lan Phuong Vu, Carina Lemke
© Volker Lannert Uni Bonn

 

 

August 2021


The junior scientist Dr. Thanigaimalai Pillaiyar (AK Prof. Müller) is a leading expert in the field of inhibitors against coronaviruses [1,2]. His promising work focuses on the Main Protease (Mpro) of SARS-CoV-2, which is essential for viral replication. The agents can pass the cell membrane and inhibit SARS-CoV-2 Mpro both reversibly and irreversibly. Thus, the enzyme is no longer available for the production of important viral proteins, and viral replication is stopped or slowed down significantly. Back in 2013, Dr. Pillaiyar developed one of the most potent inhibitors of the related SARS-CoV-1 Mpro[3]. The first novel inhibitors have already been tested in-vitro systems and show high inhibitory activity against SARS-CoV-2 Mpro.

We spoke with Dr. Pillaiyar

How did you get the idea for your corona research?

Malai: Coronaviruses have been a threat to humanity for many decades now [1,2]. But despite regular deadly outbreaks (SARS-1 in 2002, MERS in 2012) with high fatality rates (37% for MERS), there is still too little research conducted in the field. This is also the reason why we still don’t have effective treatment options against coronaviruses. We have tried to counteract this by developing potent inhibitors.

How are your preliminary works – the development of inhibitors against the related SARS-CoV-1 Mpro – useful for your efforts against SARS-CoV-2?

Malai: The works on SARS-CoV-1 Mpro [3-5] were of vital importance for us to have a viable starting point for our research against SARS-CoV-2 Mpro. The two viruses share part of their genome. Especially some important proteins are highly similar. In the case of Mpro the sequence identity is higher than 96% and even greater in the substrate binding pocket. Therefore, we expected some activity of our old inhibitors against the new virus, and we are very pleased that we could identify a lead structure so fast.

What does your research look like?

Malai: The first thing we need is a molecule that already has some sort of affinity to the desired enzyme. We can get a molecule like that from previous studies – as in our case, or via high-throughput screening, which is often employed nowadays. Virtual screening is also getting more and more important. The inhibitors of an enzyme often look very similar to its natural substrate. However, due to their greater affinity to the active site, they block the substrate from binding. The aim is to increase the affinity of the inhibitor to block the binding pocket even better and faster. Therefore, parts of the molecule are modified synthetically to engage in more interactions with the enzyme. But it is also important that, for example, the size of the molecule does not exceed a certain threshold, so as not to interfere with the passage through the cell membrane.

What is the function of Mpro? And what exactly does your inhibitor do?

Malai: Mpro is one of two proteases [1,2] that coronaviruses need to cleave the first translation product – a long polyprotein – into smaller functional and structural proteins. If this step doesn’t happen viral replication essentially stops. Our inhibitors appear structurally similar to the substrate and are recognized as such by Mpro. But they bind the enzyme so tightly, and often irreversibly, that Mpro will not part with them. Therefore, the enzyme can no longer perform its task.

How do you judge the likelihood for success of your work?

Malai: We are still at the beginning of our work on SARS-CoV-2 and there is much to be done. However, we have already developed promising agents that show even higher activity against SARS-CoV-2 Mpro than any other published compound in preliminary studies. It is important for us to increase this activity even further, keeping physicochemical properties of the compounds in mind (for solubility and bioavailability). The compounds’ selectivity against human proteases is another important factor to consider, so as to reduce possible side effects. We are working together with many research groups from around the globe, and we are confident that our work poses a valuable contribution to the fight against current and future coronavirus pandemics. 

Many thanks for the interessting interview and good luck for your further research!

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Dr. Pillaiyar
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Key References

[1] Pillaiyar, T.; Sangeetha, M.; Manickam, M. Recent discovery and development of inhibitors targeting human coronaviruses. Drug Discov. Today 2020, 25, 668-688.

[2] Pillaiyar, T.; Manickam, M.; Namasivayam, V.; Hayashi, Y.; Jung, S.-H. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy. J. Med. Chem. 2016, 59, 6595-6628.

[3] Pillaiyar, T.; Yamamoto, T.; Koiwai, Y.; Takayama, K.; Yakushiji, F.; Akaji, K.; Kawasaki, Y.; Chen,  S.-E.; Tavakolian, A. N.; Schӧn, A.; Freire, E.; Hayashi, Y.* Development of novel dipeptide-type inhibitors with novel P3-scaffolds against SARS-CoV 3CLpro: Design, synthesis, biological evaluation and molecular docking study. Eur. J. Med. Chem. 2013, 68, 372-384.

[4] Pillaiyar, T.; Yamamoto, T.; Koiwai, Y.; Takayama, K.; Yakushiji, F.; Akaji, K.; Kawasaki, Y.; Chen, S.-E.; Tavakolian, A. N.; Schӧn, A.; Freire, E.; Hayashi, Y.* Design, synthesis, and biological evaluation of dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study. Eur. J. Med. Chem. 2013, 65, 436-447.

[5] Konno, S.; Pillaiyar, T.; Nakada, K.; Yamamoto, T.; Yamazaki, Y.; Yakushiji, F.; Akaji, K.; Kiso, Y.; Kawasaki, Y.; Freire, E.; Hayashi, Y.* Design, synthesis of new tripeptide-type SARS-CoV 3CLpro Inhibitors containing an electrophilic aryl ketone moiety. Bioorg. Med. Chem. 2013, 21, 412-424.

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